JP2002512976A - Method for treating hot flashes and gynecomastia - Google Patents

Abstract

  (57) [Summary] Methods are provided for inhibiting hot flashes or gynecomastia in a subject. In the methods of the invention, an LHRH antagonist is administered to a subject in need of treatment for hot flashes or gynecomastia, such that hot flashes or gynecomastia are inhibited in the subject. In a particularly preferred embodiment, the present invention provides a method for inhibiting menopause-related hot flashes, wherein the LHRH antagonist is for preventing menopause-related hot flashes in a subject. Administered to a subject in need of treatment.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Menopausal women frequently experience a variety of symptoms due to estrogen deficiency due to ovarian failure. The most common and most characteristic symptom of menopause, which occurs in up to 85% of menopausal women, is a temporary disorder consisting of sudden hot flashes and sweating, referred to as "hot flashes". Vasomotor hot flashes are also the most frequent side effect associated with the antiestrogen drug tamoxifen, used in the treatment of breast cancer. Non-hormonal related causes of hot flashes also exist, but these are less common. One example is a deficiency or low level of alcohol dehydrogenase. People with such deficiencies can be particularly prone to climbing with alcohol uptake. Other rare causes of hot flashes include carcinoid syndrome or pheochromocytoma.

[0002] Hot flashes are most commonly treated with estrogen replacement therapy (orally, percutaneously, or via an implant), but some women may not tolerate estrogen treatment. In addition, estrogens are not usually recommended for women with hormone-sensitive cancers (eg, breast cancer). Other options have been studied for the treatment of hot flashes, including steroids, α-adrenergic agonists, and β-blockers, with varying degrees of success. Although progestins such as megestrol acetate and medroxyprogesterone have been shown to reduce hot flashes to 25-85% and 75-100%, respectively, the long-term effects of progestin treatment have not been studied. Side effects such as thromboembolic disorders, edema, weight gain, lipid changes, and death from cardiovascular disease may make the use of this treatment unattractive.

[0003] Central nor adrenergic activity
gic activity) is believed to play a role in the onset of hot flashes. Therefore, agents that inhibit the release of norepinephrine have also been used to alleviate hot flashes. CLONDINE ^™ (administered transdermally) reduced the frequency and severity of hot flashes due to tamoxifen, but the results were different for orally administered clonidine. Side effects associated with clonidine treatment include drowsiness, constipation, orthostatic hypotension, dry mouth, headache, nausea, fatigue,
And decreased libido. Methyldopa was shown to reduce hot flashes by 30%, which was accompanied by fatigue, weakness, dizziness, and nausea. There are reports of combinations of the use of naproxen β-blocker, VERALIPRIDE ^™ , and NAXOLONE ^™ .

[0004] Gynecomastia is the development of excess breast tissue in the male. There may be physiological (pubertal, aging) or pathological (drugs, tumors, liver and renal failure, hormonal imbalance) causes for this. Whatever the etiology, the underlying cause of gynecomastia is an increase in the estrogen: testosterone ratio. Surgical correction (mastectomy) is a common method of treatment, but is somewhat expensive. In recent years, liposuction has also been used as a method of treatment. However, this method does not completely treat true gynecomastia. This is because it removes fat, not breast tissue. Antiestrogens have also been tried. Tamoxifen and DANAZOL ^™ have been shown to reduce gynecomastia in about 70% of middle-aged men (Parker LN et al., Metabolism, 1).
986, 35: 705-8, Jones DJ et al., Ann Roy Coll.
Surg, 1990, 72: 286-8). CLOMIPHENE ^™ has proven unsuccessful and has been associated with deleterious side effects (Ploughre PV et al., Am. J. Dis. Child., 1983, 137: 1080-2).

[0005] Thus, a method of treatment that is effective and does not produce adverse side effects is needed for patients suffering from hot flashes or gynecomastia.

SUMMARY OF THE INVENTION [0006] The present invention provides an effective method of inhibiting hot flashes or gynecomastia in a subject suffering from these disorders. In general, the methods of treatment of the present invention provide that an LHRH antagonist is administered to a subject suffering from or at risk of having a hot flash or gynecomastia so that hot flash or gynecomastia is inhibited in the subject. Administering to the subject.

[0007] Accordingly, one aspect of the present invention is a method for inhibiting hot flashes in a subject,
It features a method of inhibiting hot flashes in a subject by administering an LHRH antagonist to the subject. In another embodiment, the present invention provides a method of treating a subject for hot flashes, wherein a subject in need of treatment for hot flashes is first selected for treatment, and then the subject is treated for hot flashes. An LHRH antagonist is administered to the subject to be treated. A subject in need of treatment for hot flashes can be a subject having a current hot flash or a subject at risk of having a hot flash. In a particularly preferred embodiment,
The present invention provides a method of treating a subject for menopause-related hot flashes. In this method, a subject in need of treatment for menopause-related hot flashes is selected, and an LHRH antagonist is administered to the subject such that the subject is treated for menopause-related hot flashes. A subject in need of treatment for menopause-related hot flashes can be a subject who is currently suffering from or at risk of having a menopause-related hot flash. In addition to treating menopause-related hot flashes, the methods of the present invention may also include hot flashes resulting from other disorders or treatments (
For example, it can be used to treat prostate cancer treatment, tamoxifen acetate treatment, alcohol dehydrogenase deficiency, or hot flashes resulting from carcinoid syndrome / pheochromocytoma).

[0008] Another aspect of the invention is directed to a method of inhibiting LHR such that gynecomastia is inhibited in a subject.
A method for inhibiting gynecomastia in a subject by administering an H antagonist to the subject. In another embodiment, the invention provides a method of treating a subject for gynecomastia, wherein a subject in need of treatment for gynecomastia is first selected for treatment, and then An LHRH antagonist is administered to the subject so that the body is treated for gynecomastia. A subject in need of treatment for gynecomastia may be a subject who is currently suffering from gynecomastia or a subject at risk of having gynecomastia. In a preferred embodiment, the gynecomastia in the subject is the result of a hormonal balance.

[0009] Any LHRH antagoni that effectively inhibits the activity of the LHRH-R receptor
A strike may be used in the method of the present invention. However, in a particularly preferred embodiment
Wherein the LHRH antagonist has the structure: Ac-D-Nal¹, 4-Cl-D
-Phe^Two, D-Pal^Three, N-Me-Tyr^Five, D-Asn⁶, Lys (iPr) ⁸ , D-Ala^TenHas LHRH (referred to herein as PPI-149)
You.

[0010] In another preferred embodiment of the invention, the subject is a mammal, for example, most preferably a human.

In yet another preferred embodiment, the LHRH antagonist is administered to a subject by a parenteral route, preferably by injection, most preferably by intramuscular or subcutaneous / intradermal injection.

[0012] In yet another preferred embodiment, the LHRH antagonist is administered to a subject in a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation can be a dispersion. For example, the formulation may be a lipid-based (eg, a liposome formulation)
Or it may be polymer based (eg, polymer microspheres). In a particularly preferred embodiment, the formulation comprises the LHRH antagonist in an insoluble complex with an anionic carrier polymer (eg, carboxymethylcellulose).

In a preferred embodiment, the LHRH antagonist is, for example, about 15-3
00 μg / kg / day, 15-200 μg / kg / day, or 15-100 μg / day
It is administered at a dosage of kg / day. The LHRH antagonist can be administered continuously using a sustained release formulation, such as a formulation in an osmotic pump or a formulation that allows for a slow release of the LHRH antagonist into the tissue of the subject. For sustained treatment of a subject, the LHRH antagonist may be administered to the subject for at least 1 month, preferably 3 months or more, and even more preferably 6 months. To achieve long-term sustained treatment, it may be necessary to re-administer the sustained release formulation. For example, a sustained release formulation that delivers an LHRH antagonist for a one month period can be re-administered on a monthly basis to achieve sustained treatment for several months (eg, six months). Similarly, a sustained release formulation that delivers an LHRH antagonist for a period of one week may be re-administered on a weekly basis to achieve sustained treatment for several weeks. Sustained release formulations provided herein (see, eg, Example 3) can deliver an LHRH antagonist for a period of at least about one month, and thus achieve long-term treatment. It can be re-dosed on a monthly basis.

[0014] The LHRH antagonist can be administered to a subject alone or in combination with at least one other therapeutic agent. Examples of other therapeutic agents that can be administered with an LHRH antagonist include LHRH agonists, anti-androgens, antiestrogens, and inhibitors of sex steroid biosynthesis.

[0015] In another embodiment, the LHRH antagonist is administered in combination with a sex hormone (eg, estrogen or testosterone). For example, estrogen replacement therapy is often used during (and after) menopause to alleviate certain symptoms associated with menopause, and thus is one embodiment of the present invention,
It is treated with both estrogen (and / or other related female sex hormones such as progesterone) and LHRH antagonists. The use of an LHRH antagonist in combination with an estrogen (and / or other related female sex hormones) may tolerate the use of lower dosages of the hormone than when the hormone is used alone. A similar combination of treatments can be used in disorders where testosterone (and / or other related male hormones) is administered.

[0016] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of inhibiting hot flashes or gynecomastia in a subject. The methods of the invention generally comprise administering an LHRH antagonist to the subject such that hot flashes or gynecomastia are inhibited in the subject. In certain embodiments, the methods of the present invention comprise the steps of selecting a subject in need of treatment for hot flashes or gynecomastia, and administering an LHRH antagonist such that the subject is treated for hot flashes or gynecomastia. Administering to the subject. The methods of the present invention for treating hot flashes can be used, for example, to treat hot flashes resulting from menopause, tamoxifen acetate treatment, prostate cancer treatment, alcohol dehydrogenase deficiency, or carcinoid syndrome / chromochromocytoma. The methods of the invention for treating gynecomastia can be used, for example, to treat gynecomastia resulting from hormonal imbalance.

[0018] The exact pathophysiology of hot flashes is unknown, but it appears to be related to changes in the settings of the thermoregulation center located in the hypothalamus. Blood collection in women who experience hot flashes indicates that the onset of hot flashes is due to the release of gonadotropin releasing hormone (GnRH) in the hypothalamus and subsequent luteinizing hormone (LH) pulse (pu
1se). This increase in the level of LH is believed to cause a decrease in the setting of the temperature control center. When trying to restore equilibrium,
A hot flash is generated. Although not intended to be limited by any mechanism, the L
It is believed that the ability of the HRH antagonist to inhibit hot flashes results, at least in part, from its inhibition of the LH pulse, which reduces the set point of the thermoregulation center.

As used herein, the term “LHRH antagonist” refers to a compound that inhibits luteinizing hormone releasing hormone receptor, thereby inhibiting luteinizing hormone release. The term "LHRH antagonist" refers to a compound that inhibits LHRH-R such that the release of LH is inhibited, so that the term "LHRH-
R antagonist "can be used interchangeably. LHRH antagonists have been described in the art; see, for example, US Patent No. 5 to Folkers et al.
U.S. Patent No. 5,843,901 to Roeske et al .; U.S. Patent No. 5,413,990 to Haviv; U.S. Patent No. 5,300,492 to Haviv; U.S. Patent No. 5 to Koerber et al. , 37
U.S. Pat. No. 5,296,468 to Hoeger et al .; Ja.
U.S. Pat. No. 5,171,835 to Naky et al .; U.S. Pat. No. 5,003,011 to Coy et al .; U.S. Pat. No. 4,431,635 to Coy;
U.S. Patent No. 4,992,421 to De et al .; U.S. Patent No. 4,851,385 to Roeske; Nestor, Jr. U.S. Pat.
And U.S. Patent No. 4,689,396 to Roeske et al.
See issue.

For example, preferred LHRH-R antagonists that can be used in the methods of the present invention include peptides having the structure: ABCDCEFGFHIJ or pharmaceutically acceptable Wherein A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar,
Or Ac-D-Pal; B is His or 4-Cl-D-Phe; C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O)
Or D-Trp, D is Ser, E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iP
r), 4-Cl-Phe, His, Asn, Met, Ala, Arg, or I
le; F is

[0021]

Embedded imageWherein R and X are independently H or alkyl; and Y includes a bipolar moiety; G is Leu or Trp; H is Lys (iPr), Gln, Met, or Arg; I is Pro; and J is Gly-NH_TwoOr D-Ala-NH_TwoIt is. In a preferred embodiment
And Y is ylide, tertiary amine oxide, nitrile oxide, pyridine-N-O
Selected from the group consisting of oxides and pyridinium zwitterions. Especially preferred
In certain embodiments, Y is ylide, pyridine-N-oxide, or pyridinyl.
Is a zwitterion. In a preferred embodiment, the peptide has the structure: Ac-D-Nal-4-Cl-Phe-D-Pal-Ser-Tyr-DP
al (NO) -Leu-Lys (iPr) -Pro-D-Ala-NH_Two including. In another preferred embodiment, the peptide has the structure: Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D
-Pal (CH_TwoCOO^-) -Leu-Lys (iPr) -Pro-Ala-NH _Two Or a pharmaceutically acceptable salt thereof.

In another aspect, the LHRH-R antagonist used in the methods of the present invention is a peptide or pharmaceutically acceptable peptide having the structure: ABCD-DEFGHHIJ And acceptable salts thereof, wherein A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar,
Or Ac-D-Pal; B is His or 4-Cl-D-Phe; C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O)
Or D-Trp, D is Ser, E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iP
r), 4-Cl-Phe, His, Asn, Met, Ala, Arg, or I
F is D-Arg, D-Lys (iPr), D-Pal (iPr), D-Ci
t or Q, where Q is a structure

[0023]

Embedded image Wherein R and X are independently H or alkyl; and Z comprises a cationic moiety selected from the group consisting of a cationic pyridinium moiety and a sulfonium moiety, provided that the cationic moiety Is not N-methylpyridinium; G is Leu or Trp; H is Lys (iPr), GIn, Met, Arg, or Q: I is Pro; and J is Gly- NH ₂ or D-Ala-NH ₂ ; provided that at least one of F and H is Q.

In a preferred embodiment, F is Q and Z is a cationic pyridinium moiety. In a preferred embodiment, Z is an N-benzylpyridinium moiety. In another preferred embodiment, F is Q and Z is
It is a sulfonium moiety. In still other preferred embodiments, H is Q and Z is a sulfonium moiety. In a particularly preferred embodiment, the peptide has the structure Ac-Sar-4-Cl-D-Phe-D-Nal-Ser-Tyr-DP
al (Bzl) -Leu-Lys (iPr) -Pro-Ala-NH ₂ ; or a pharmaceutically acceptable salt thereof. In another particularly preferred embodiment,
The peptide has the structure: Ac-D-Nal-4-Cl-D-Phe-D-Trp-Ser-Tyr-D
Including or a pharmaceutically acceptable salt ^{thereof; -Met (S + Me) -Leu} -Arg-Pro-Ala-NH 2. In a particularly preferred embodiment, the peptide has the structure: Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D
Including or a pharmaceutically acceptable salt thereof; -Arg-Leu-Met (S + Me) -Pro-Ala-NH 2.

In another aspect, the LHRH-R antagonist used in the methods of the present invention is a peptide or pharmaceutically acceptable peptide having the structure: ABCDCEFGHHIJ Wherein A is p-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar, or Ac-D-Pal, and B is His or 4- Cl-D-Phe, C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (NO)
Or D-Trp, D is Ser, E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iP
r), 4-Cl-Phe, His, Asn, Met, Ala, Arg, or I
le, and F is

[0026]

Embedded image Wherein R and X are independently H or alkyl; and T comprises a receptor modifying moiety; G is Leu or Trp; H is Lys (iPr), Gln , Met, or be Arg: I is an Pro; and J is Gly-NH ₂ or D-Ala-NH _2.

In a preferred embodiment, T is selected from the group consisting of an ylide, a sulfonium moiety, an α-halocarbonyl, a sulfate, a sulfonate, an alkyl halide, and a benzyl halide. In a particularly preferred embodiment, T is α-halocarbonyl.

In another embodiment, the LHRH-R antagonist used in the method of the invention is a peptide or a pharmaceutical comprising the structure: ABCD-E-F-F-G-H-I-J Wherein A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar,
Or Ac-D-Pal; B is His or 4-Cl-D-Phe; C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O)
Or D-Trp, D is Ser, E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iP
r), 4-Cl-Phe, His, Asn, Met, Ala, Arg, or I
le, and F is

[0029]

Embedded image Wherein R and X are independently H or alkyl; and M comprises an N-acyl hydrophilic moiety; G is Leu or Trp; H is Lys (iPr) , Gln, there Met or Arg,: I is an Pro; and J is Gly-NH ₂ or D-Ala-NH _2.

In another aspect, the LHRH-R antagonist used in the methods of the present invention is a peptide or pharmaceutically acceptable peptide having the structure: ABCDCEFIGHIJ And acceptable salts thereof, wherein A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar,
Or Ac-D-Pal; B is His or 4-Cl-D-Phe; C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O)
Or D-Trp, D is Ser, E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iP
r), 4-Cl-Phe, His, Asn, Met, Ala, Arg, or I
le, and F is

[0031]

Embedded image Wherein R and X are independently H or alkyl; and L comprises a small polar moiety; G is Leu or Trp; H is Lys (iPr), Gln, Met, or be Arg: I is an Pro; and J is Gly-NH ₂ or D-Ala-NH _2.

In a preferred embodiment, L is selected from the group consisting of D-Cit, D-Asn, D-Gln, and D-Thr.

Preferred LHRH antagonists have good LHRH antagonist activity and
And low histamine release activity (eg, at least 3 μg / ml, more preferably
At least 5 μg / ml, and even more preferably at least 10 μg / m
of histamine release in a standard in vitro histamine release assay.
ED₅₀) And are water-soluble LHRH antagonists. L
The efficacy of candidate LHRH antagonists in inhibiting H release is, for example, Co
rbin and Beattie, Endocrine Res. Commun.
2: 1 (1975), in an animal model as described in
Can be In this assay, the LHRH antagonist activity of the candidate compound is:
By measuring the antiovulatory activity (AOA) of the compound in rats,
Will be sedated. Preferably the histamine releasing activity is determined by the US patent to Roeske.
Assayed by the method described in US Pat. No. 4,851,385. Low
As preferred LHRH antagonists with histamine releasing activity and water solubility
Is described in PCT Publication WO 96/40757 (the entire contents of which are
Which are expressly incorporated by reference). In particular
Preferred LHRH antagonists have the structure: Ac-D-Nal¹, 4-Cl-D
-Phe^Two, D-Pal^Three, N-Me-Tyr^Five, D-Asn⁶, Lys (iPr) ⁸ , D-Ala^Ten-LHRH (referred to as PPI-149 and U.S. Pat.
843,901).

Alternatively, the methods of the present invention can be used with any of a variety of compounds known in the art to have LHRH antagonist activity. These LH
RH antagonists are typically analogs of the LHRH decapeptide; non-limiting examples include Antide, Nal-Glu (structure: Ac-DN
al (2) ¹ , 4-Cl-D-Phe ² , D-Pal ³ , Arg ⁵ , D-Glu ⁶ (
AA), having a D-Ala ¹⁰ -LHRH), and SB-75 (CETROR
(Also known as ELIX ^™ ) (structure: Ac-D-Nal ¹ , 4-Cl-D-
Phe ² , D-Pal ³ , D-Cit ⁶ , D-Ala ¹⁰ -LHRH). Another example of LHRH antagonists which may be used in the methods of the present invention has the ^{structure: Ac-D-Nal 1,} 4-Cl-D-Phe 2, D-Pal 3, N-M
e-Tyr ⁵ , D-Lys (N-ε-nicotinoyl) ⁶ , Lys (iPr) ⁸ , D
-Ala ¹⁰ -LHRH (further described in European Patent EP 400 065 B).

As used herein, the term “inhibit” (as in “inhibit hot flashes” or “inhibit gynecomastia”) reduces or reduces hot flashes or gynecomastia. It is intended to mean to regulate. The term “inhibit” is intended to include both partial and complete inhibition.

As used herein, the term “treat” refers to treating a subject with a specific therapeutic regimen for the purpose of reducing symptoms or preventing a particular condition. Exposure.

As used herein, the term “subject” is intended to include animals, preferably mammals, most preferably humans, afflicted with hot flashes and / or gynecomastia. . In a preferred embodiment, the subject is a primate. In an even more preferred embodiment, the primate is a human. Other examples of subjects include dogs, cats, goats, and cows.

[0038] The term "hot flashes" is an art-recognized term that refers to a temporary impairment in body temperature that typically consists of a sudden rise in body temperature, usually with sweating in the subject.

As used herein, the term “antiestrogen” refers to a compound that antagonizes estrogen release or action. Antiestrogens are known in the art (eg, tamoxifen and its derivatives (eg, trioxyphen, toremifene, and droloxifene)), and are commercially available (eg, tamoxifen; trade names: NOLVADEX ^™ , ICI). Pharm
products of Aceuticals).

As used herein, the term “antiandrogen” refers to a compound that antagonizes androgen release or action. Anti-androgens are known in the art (see, for example, US Pat. No. 4,386,080).
And commercially available (eg, ANDORCUR ^™ , Schering A)
. G. FIG. Products), and steroidal and non-steroidal anti-androgenic substances. A specific example of a nonsteroidal androgen is flutamide (4
'-Nitro-3'-trifluoromethylisobutylanilide; trade name EULEXI
N ^™; Schering-Plough), bicaltamide
de), and nilutamide.

As used herein, the term “LHRH agonist” refers to luteinizing
Stimulates luteinizing hormone-releasing hormone receptor so that hormones are released
(Eg, a compound that mimics the activity of LHRH). LHRH Agoni
The strike may have a stronger LH releasing activity than native LHRH ("Super Agoni
Strike). Many LHRH agonists and super agonists
Are known in the art. Commercially available LHRH agonists include Leupe
Lourido (product name: LUPRON)^TMAbbott / T;
AP), goserelin (trade name: ZOLADEX)^TMZe
neca), buserelin (Hoechst), trypto
Relin (decapeptyl, D-Trp-6-LHRH and DEBIOPHARM ^TM ; Nafarelin (also known as Ipsen / Beaufour);
Name "SYNAREL^TMSyntex), lutrelin (W)
yesth), cistrelin (Hoechst), Gonna
Gonororelin (Ayerst) and histrelin (
histrelin) (Ortho).

The term “inhibitors of sex steroid biosynthesis” refers to inhibitors of adrenal sex steroid biosynthesis (eg, aminoglutethimide), and inhibitors of testicular sex steroid biosynthesis (eg, ketoconazole), or a combination thereof. It is intended to include matching.

Pharmaceutically Acceptable Formulations In the methods of the present invention, the LHRH antagonist is typically administered in a pharmaceutically acceptable formulation. Pharmaceutically acceptable formulations of the present invention typically include an LHRH antagonist and a pharmaceutically acceptable carrier, and are any formulation compatible with pharmaceutical administration (eg, a polymer conjugate, Including synthetic or natural polymers in the form of nanocapsules, microspheres, or beads), and lipid-based formulations (including oil-in-water emulsions, micelles, mixed micelles, synthetic membrane vesicles, and released red blood cells) ).

In a particularly preferred embodiment, the pharmaceutical formulation comprises a carrier polymer, preferably an anionic polymer (eg, US patent application Ser. No. 08 / 762,747 and corresponding PCT application No. PCT / US97 / 22881 (these are incorporated herein by reference). Both contents of
LHRH antagonists (preferably of the structure Ac-D-Nal ¹ , 4-Cl-D-) in a water-insoluble complex with carboxymethylcellulose, which is explicitly described herein by reference). Phe ² , D-Pal ³ , N-Me-Ty
r ^5, including ^{D-Asn 6, Lys (iPr} ) 8, with a D-Ala ¹⁰ -LHRH). Briefly, a complex of an LHRH antagonist and a carrier polymer is formulated by combining the LHRH antagonist and the carrier polymer under conditions such that a substantially water-insoluble compound is formed, for example, an LHRH antagonist And an aqueous solution of the carrier polymer are mixed until the complex precipitates. The complex can be in solid form (eg, a paste, granule, powder, or lyophilizate), or the powdered form of the complex forms a stable liquid suspension or semi-solid dispersion. Can be ground finely enough. The complex is stable to sterilization, such as by gamma irradiation or electron beam irradiation, prior to administration in vivo. Preferred carrier polymers for use in this conjugate are anionic polymers or fragments thereof, such as anionic polyalcohol derivatives, and salts thereof (eg, sodium salts). Anionic moieties from which polyalcohols can be derivatized include, for example, carboxylic acid groups, phosphate groups or sulfate groups. Particularly preferred anionic polymers are anionic polysaccharide derivatives or fragments thereof, and salts thereof (eg, sodium salts). The carrier polymer can include a single molecular species (eg, a single type of polymer), or two or more different molecular species (eg, a mixture of two types of polymers). Examples of particular anionic polymers include carboxymethylcellulose, algin, alginate, anionic acetate polymer, anionic acrylic polymer, xanthan gum, sodium starch glycolate, and fragments thereof,
Derivatives, and pharmaceutically acceptable salts, and anionic carrageenan derivatives, anionic polygalacturonic acid derivatives, and sulfated and sulfonated polystyrene derivatives. A preferred anionic polymer is carboxymethylcellulose sodium salt. In certain embodiments, the carrier polymer,
Preferably sodium carboxymethylcellulose, and an LHRH antagonist, preferably PPI-149, comprise 0.2: 1 (w / w) carrier polymer:
Combined in peptide compound ratio. In various other embodiments, the ratio of carrier polymer: peptide compound (w / w) is, for example, 0.5: 1, 0.4: 1,
It can be 0.3: 1, 0.25: 1, 0.15: 1 or 0.1: 1. In another preferred embodiment, the solid ionic complex of the LHRH antagonist and the carrier polymer has a peptide content of 57% by weight, 60% by weight, 65% by weight, 70% by weight.
% By weight, 75% by weight, 79% by weight or more. In still other preferred embodiments, the solid ionic complex of the LHRH antagonist and the carrier polymer has a peptide content of 57-79% by weight. This formulation of an LHRH antagonist and a carrier polymer has the added advantage of providing sustained delivery of the LHRH antagonist to the tissue of the subject to which it is administered.

In another embodiment, the pharmaceutically acceptable formulation comprises a polymer matrix. The term "polymer" or "polymeric" is art-recognized and includes a structural framework composed of repeating monomer units. The term also includes copolymers and homopolymers (eg, those that are synthetic or naturally occurring). Linear, branched, and crosslinked polymers are also meant to be included. For example, polymeric materials suitable for forming the pharmaceutically acceptable formulations used in the present invention include naturally occurring polymers such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and Polysaccharides), as well as synthetic polymers (eg,
Polyester (PLA, PLGA), polyethylene glycol, poloxomer (
poloxomers, polyanhydrides, and pluronics
). These polymers are biocompatible, biodegradable and do not produce any toxic degradation by-products, and by manipulating the kinetic characteristics of the polymer, they can modulate and sustain the release of LHRH antagonists. Have the ability to modify the period. As used herein, the term "biodegradable" refers to the fact that a polymer is produced in the body of a subject by the action of enzymes, by hydrolysis,
And / or by other similar mechanisms.
As used herein, the term "biocompatible" refers to a living tissue or living organism by virtue of the polymer not being toxic or damaging, and not causing immunological rejection. Means conformance.

Polymers can be prepared by methods known in the art (Sandler, SR; Ka).
ro, W.R. Polymer Syntheses; Harcourt Bra
ce: Boston, 1994; Shalaby, W.C. Ikada, Y .; L
angel, R.A. Williams, J .; Polymers of Biol
official and Biomedical Significance (
ACS Symposium Series 540; American Ch
Chemical Society; Washington, DC, 1994). The polymer can be designed to be flexible; the distance between the bioactive side chains, and the length of the linker between the polymer backbone and the group can be controlled. Other suitable polymers and methods for their preparation are described in US Pat.
Nos. 5,044 and 5,576,018.

[0047] The formulation of the polymer may be, for example, an active ingredient (eg, an LHRH antagonist) within the liquefied polymer, as described in US Pat. No. 4,883,666.
Or by Odian G. , Principles of Po
lymerization and ring opening Polyme
Rizzation, 2nd edition, John Wiley & Sons, New Y
ork, 1981, bulk polymerization, interfacial polymerization, solution polymerization,
And by methods such as cyclic polymerization. The properties and characteristics of the formulation are controlled by varying parameters such as reaction temperature, concentration of polymer and LHRH antagonist, type of solvent used, and reaction time.

An LHRH antagonist is encapsulated in one or more pharmaceutically acceptable polymers to form microcapsules, microspheres, or microparticles (terms used interchangeably herein). Can be Microcapsules, microspheres, and microparticles are conventional free flowing powders composed of spherical particles less than 2 millimeters in diameter, usually less than 500 microns in diameter. Particles smaller than one micron are conventionally referred to as nanocapsules, nanoparticles, or nanospheres. For the most part, the difference between microcapsules and nanocapsules, between microspheres and nanospheres, or between microparticles and nanoparticles is large; in general, if any, There is little difference between the two internal structures.

[0049] In another embodiment, the pharmaceutically acceptable formulation comprises a lipid-based formulation. Any known lipid-based drug delivery system can be used in the practice of the present invention. For example, multivesicular liposomes (MVL), multilamellar liposomes (also known as multilamellar vesicles or "MLV"), unilamellar liposomes (small unilamellar liposomes (also known as unilamellar vesicles or "SUV") and large Unilamellar liposomes (including large unilamellar vesicles or also known as "LUVs") can be used in their entirety, as long as a sustained release rate of the encapsulated LHRH antagonist can be established. In one embodiment, the lipid-based formulation can be a multilayer vesicle liposome system. Methods for making controlled release multi-layer vesicle liposome drug delivery systems are described in patent applications WO 9513796 and W.
O9703652.

The composition of the synthetic membrane vesicle is usually a combination of phospholipids, usually in combination with steroids, especially cholesterol. Other phospholipids or other lipids can also be used. Examples of lipids useful in producing synthetic membrane vesicles include phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides. Preferred phospholipids including egg phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and dioleoylphosphatidylglycerol are used.

In preparing lipid-based vesicles containing an LHRH antagonist, the efficiency of LHRH antagonist encapsulation, the instability of the LHRH antagonist, the homogeneity and size of the resulting vesicle population, the LHRH antagonist of the preparation: Variables such as ratio, permeability, instability, and the pharmaceutical acceptability of the formulation should be considered (Szoka et al., Annual Revi.
ews of Biophysics and Bioengineering
s, 9: 467, 1980; Deamer et al., Liposomes, Marce.
I Dekker, New York, 1983, 27; and Hope et al., C
hem. Phys. Lipids, 40:89, 1986).

Other formulations include controlled release compositions (referred to as “slow release formulations”) as are known in the art for administration of leuprolide (Lupron®), eg, Capsules (US Pat. Nos. 4,652,441 and 4,917,893), injectable formulations (US Pat. No. 4,849)
228), lactic acid-glycolic acid copolymers useful in making microcapsules or injectable formulations (U.S. Pat. Nos. 4,677,191 and 4,728,721), and water-soluble poly Sustained release compositions for peptides (US Pat. No. 4,675,189). Particularly preferred sustained release formulations include an LHRH antagonist in a water-insoluble complex with an anionic carrier polymer (see above and in US patent application Ser. No. 08 / 762,747 and PCT patent application PCT / US97 / 22881). Further described).

[0053] In addition to the LHRH antagonist and a pharmaceutically acceptable carrier, the pharmaceutically acceptable formulation used in the methods of the present invention may comprise additional pharmaceutically acceptable reagents and / or excipients. May be included. As used herein,
"Pharmaceutically acceptable reagents and / or excipients" refers to any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents,
Isotonic agents (eg, sugars, polyalcohols (eg, mannitol, sorbitol))
Or sodium chloride) and absorption delaying agents (eg, monostearate and gelatin) and the like. Excipients include pharmaceutically acceptable stabilizers and disintegrants. Precise fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Except insofar as any conventional vehicle or agent is incompatible with the active compound (eg, an LHRH antagonist), its use in the pharmaceutical compositions of the present invention is contemplated.

Administration of a Pharmaceutically Acceptable Formulation The LHRH antagonist can be administered to a subject as needed and, preferably, a sustained release formulation (eg, an LHRH antagonist and an anionic carrier high). Formulations containing water-insoluble complexes with molecules, slow release polymers (eg, poly-
Lactide polymer, poly-glycolide polymer, and poly-lactide / poly-
Glycolide copolymer), an osmotic pump, an implant, or a formulation in a transdermal patch). Sustained-release formulations are administered by any suitable route for continuous release of the drug in a subject, such as subcutaneous injection or implantation. Pharmaceutically acceptable formulations can be readily suspended in aqueous vehicles and are introduced via a conventional hypodermic needle or by using an infusion pump. Prior to introduction, the formulation may be sterilized, preferably by gamma irradiation or electron beam sterilization as described in U.S. Patent No. 436,742. For injection, the LHRH antagonist formulation may be formulated in a liquid solution, preferably in a physiologically compatible buffer such as Hanks' solution or Ringer's solution. In addition, LHRH antagonist formulations can be formulated, for example, in solid form, which is lyophilized and rapidly redissolved or suspended prior to use. Injections can be, for example, in the form of a bolus injection or continuous infusion (eg, using an infusion pump) of the LHRH antagonist formulation.

When properly formulated, an LHRH antagonist can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The LHRH antagonist (and other ingredients) can also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the LHRH antagonist may be incorporated with excipients and taken orally ingestible tablets, buccals, troches,
It can be used in the form of capsules, elixirs, suspensions, syrups, wafers and the like. The percentage of LHRH antagonist in the compositions and preparations may, of course, vary. LHR in such therapeutically useful compositions
The amount of H antagonist is such that a suitable dosage will be obtained.

To administer an LHRH antagonist by other than parenteral administration, LHRH
The antagonist may require coating the compound with a material to prevent its inactivation, or co-administering the material with the compound.

In one embodiment of the method of the present invention, an LHRH antagonist (typically in a pharmaceutical formulation) alone is administered to a subject. In another embodiment,
The method of the invention involves the administration of an LHRH antagonist in combination with one or more other therapeutic agents. Examples of other therapeutic agents that can be combined with LHRH antagonist treatment include antiestrogens (eg, used in the treatment of estrogen-dependent tumors or in the treatment of gynecomastia), anti-androgens, LHRH agonists Or inhibitors of sex steroid biosynthesis. If an inhibitor of corticosteroid biosynthesis is used, it may be desirable to co-administer hydrocortisone to the patient in an amount sufficient to maintain normal glucocorticoid levels.

Duration and Level of Administration In another embodiment of the present invention, the pharmaceutically acceptable formulation comprises a sustained delivery (
For example, "slow release" of an LHRH antagonist to a subject is provided. Preferably, the formulation comprises sustained delivery of the LHRH antagonist for at least one week, more preferably at least two weeks, and even more preferably at least one month after the pharmaceutically acceptable formulation is administered to the subject. I will provide a. In various embodiments, the subject can be treated with the LHRH antagonist for at least one month, at least three months, or at least six months.

As used herein, the term “sustained delivery” is intended to include continuous delivery of the LHRH antagonist in vivo over a period after administration. Sustained delivery of an LHRH antagonist can be demonstrated, for example, by the sustained therapeutic effect of the LHRH antagonist over time (eg, sustained delivery of an LHRH antagonist can be accompanied by hot flashes or continuous gynecomastia over time). Can be demonstrated by suppression). Alternatively, sustained delivery of the LHRH antagonist may be demonstrated by detecting the presence of the LHRH antagonist in vivo over time.

The pharmaceutical formulation used in the method of the present invention may comprise a therapeutically effective amount of LH
Including RH antagonists. “Therapeutically effective amount” refers to an amount that is effective at dosages and for periods of time necessary to achieve the desired result. A therapeutically effective amount of an LHRH antagonist is dependent on the disease state, age, and weight of the subject, as well as L
The HRH antagonist may vary according to factors such as the ability to elicit the desired response in the subject (alone or in combination with one or more other therapeutic agents). Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the LHRH antagonist. A non-limiting range for a therapeutically effective amount of an LHRH antagonist is 0.01 μg / kg to 10 mg / kg.
kg, preferably between about 0.01 and 5 mg / kg. In a preferred embodiment, the dosage of the LHRH antagonist is about 15-300 μg / kg / day,
More preferably about 15-200 μg / kg / day, and even more preferably about 15-100 μg / kg / day. A preferred dosage is 30 μg / kg
/ Day, 50 μg / kg / day, or 100 μg / kg / day. It is to be noted that dosage values may vary with the severity of the condition to be alleviated. For any particular subject, the particular dosage regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering and supervising the administration of the LHRH antagonist, and It is to be further understood that the dosage ranges set forth in the specification are exemplary only and are not intended to limit the scope and practice of the claimed invention.

[0061] Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic condition. . It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, "dosage unit form" refers to physically discrete units adapted as unitary dosages for the mammalian subject to be treated; A predetermined amount of an LHRH antagonist, calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. The specifications for the dosage unit forms of the present invention include (a) the unique properties of the particular LHRH antagonist used and the particular therapeutic effect to be achieved, and (b) hot flashes and gynecomastia in the subject The synthesis of such LHRH antagonists for the treatment of is governed by and directly dependent on the limitations inherent in the art.

The present invention is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, patents, and published patent applications cited throughout this application are hereby incorporated by reference.

[0063]

【Example】

(Example 1) In this example, patients with metastatic prostate cancer in D1 or D2 stage,
Alternatively, patients with elevated prostate-specific antigen (PSA) after radiation therapy, radical prostatectomy, or other local treatment are administered for a sustained period of time (
The LHRH antagonist PPI-149 was treated at a dosage of either 30 mg / kg / day or 50 mg / kg / day, for example, for 14 or 28 days). Other patients were treated with the LHRH agonist leuprolide or with both PPI-149 and leuprolide.

During the course of the treatment, patients were asked to fill out an endocrine-related questionnaire examining symptoms associated with changes in androgen levels, including the occurrence of hot flashes. (Other symptoms examined include fatigue, loss of libido, loss of sexual performance, smaller testis size, altered or diluted hair, decreased muscle mass, decreased muscle tone, increased or decreased weight, Urine frequency, urgency, urinary hesitation, and nocturnal enure). A summary of the results for the development of hot flashes in patients treated with either PPI-149 alone, leuprolide alone, or PPI-149 in combination with leuprolide is summarized below:

[0065]

[Table 4] This data demonstrates that patients treated with the LHRH antagonist PPI-149 alone did not experience hot flashes, while more than half of the patients treated with the LHRH agonist leuprolide experienced hot flashes. Although not intended to be limited by the mechanism, the occurrence of hot flashes is caused by circulating luteinizing hormone (LH
) And / or fluctuations in levels of follicle-stimulating hormone (FSH), resulting in at least in part, LHRH antagonists (which cause minor fluctuations in LH and / or FSH levels associated with the use of LHRH agonists) Without inhibiting the activity of the LHRH receptor), these fluctuations in LH and / or FSH levels may occur in any case where they may be clinically possible (eg, menopausal women experiencing hot flashes). Or in postmenopausal women or other populations of patients experiencing hot flashes).

Example 2: Patients with stage D1 or D2 metastatic prostate cancer, or radiotherapy,
Patients with elevated prostate specific antigen (PSA) levels after radical prostatectomy or other local treatments are treated with the LHRH antagonist PPI-149 as described in Example 1; Questions were asked regarding the development of gynecomastia. These results were compared with data obtained for patients treated with the LHRH agonist leuprolide. The results demonstrated that patients treated with PPI-149 experienced a lesser degree of gynecomastia than patients treated with leuprolide accumulation.

Example 3: To prepare a sustained release LHRH antagonist formulation, a 100 ml solution of the LHRH antagonist PPI-149 was added to 6.25 mg / ml PPI- in water.
149 was dissolved. USP Sodium Carboxymethyl Cellulose (CMC) (Low Viscosity Grade, Hercules Chemical Co
. A) (min. 100 ml) was prepared at 0.125% w / v and mixed until dissolved. Equal proportions of the PPI-149 and CMC solutions were mixed (giving a CMC: peptide ratio of 0.2: 1 (w / w)) and a solid material was obtained. The solid material was stirred overnight and then collected by filtration through a 0.45 micron nylon filter. HPLC evaluation of the filtrate of this solution indicated that at least 95% of the PPI-149 compound had been converted to a solid complex and removed from solution. The recovered white paste was rinsed twice with water and transferred to a vial and dried under reduced pressure. Upon drying for 72 hours, 633 mg of a white powder was obtained. This solid material was then powdered in a mortar and udder. Component analysis showed 57% peptide in the conjugate.

Example 4 In this example, a patient with stage D1 or stage D2 metastatic prostate cancer,
Alternatively, patients with elevated prostate-specific antigen (PSA) after radiation therapy, radical prostatectomy, or other local treatment are treated for a sustained period of time (eg, 4
Weeks, 8 weeks, or 85 days), and was treated with the LHRH antagonist PPI-149 at a dosage of either 50 mg or 50-100 mg. Another patient was treated with the LHRH agonist leuprolide (LUPRON ^™ ), with or without anti-androgen.

During the course of treatment, patients were asked to fill out a questionnaire to look for symptoms such as frequency, severity, and duration of hot flashes. A summary of the results for the appearance of hot flashes in patients treated for 4 weeks with either PPI-149 alone or leuprolide in combination with an antiandrogen is summarized in Table I below:

[0070]

[Table 1] A summary of the results for hot flash severity in patients treated for 4 weeks with either PPI-149 alone or leuprolide in combination with an anti-androgen is summarized in Table II below:

[0071]

[Table 2] A summary of the results for the duration of hot flashes in patients treated for 4 weeks with either PPI-149 alone or leuprolide in combination with an anti-androgen is summarized in Table III below:

[0072]

[Table 3] These data indicate that during the first 4 weeks of treatment, the LHRH antagonist PP
It demonstrates that patients treated with I-149 alone experienced hot flashes less frequently than patients treated with leuprolide and anti-androgen. further,
Hot flashes in patients treated with PPI-149 alone were less severe than those in patients treated with leuprolide and antiandrogens and continued for a shorter period of time.

Equivalents The skilled artisan will recognize many equivalents to the specific embodiments of the invention described herein, or will be able to ascertain using only routine experimentation. It is possible. Such equivalents are intended to be encompassed by the following claims.

Claims (26)

[Claims] 1. A method for inhibiting hot flashes in a subject, comprising administering an LHRH antagonist to the subject such that hot flashes are inhibited in the subject. 2. A method of treating a subject for hot flashes, comprising: (a) selecting a subject in need of treatment for hot flashes; and (b) providing an LHRH antagonist to the subject. Administering, wherein the subject is treated for hot flashes. 3. A method of treating a subject for menopause-related hot flashes, comprising: (a) selecting a subject in need of treatment for menopause-related hot flashes;
And (b) administering an LHRH antagonist to the subject, whereby the subject is treated for menopause-related hot flashes. 4. The LHRH antagonist has the structure: Ac-D-Nal ¹
, 4-Cl-D-Phe 2, D-Pal 3, N-Me-Tyr 5, D-Asn 6, L
ys (iPr) ^8, with a D-Ala ¹⁰ -LHRH, claim 2 or 3,
The method described in. 5. The method according to claim 1, wherein said subject is a human. 6. The method of claim 1, wherein the hot flash is the result of menopause. 7. The hot flash is a result of tamoxifen acetate treatment.
The method according to claim 1. 8. The method of claim 1, wherein the hot flash is the result of a prostate cancer treatment. 9. The method according to claim 1, wherein the hot flash is a result of alcohol dehydrogenase deficiency. 10. The method of claim 1 or 2, wherein the hot flash is the result of carcinoid syndrome / chromochromocytoma. 11. The method of claim 1, 2, or 3, wherein the LHRH antagonist is administered to a subject by a parenteral route. 12. The method of claim 11, wherein the LHRH antagonist is intramuscular injection, intradermal injection,
4. The method of claim 1, 2, or 3, wherein the method is administered to the subject by subcutaneous injection. 13. The method of claim 1, 2, or 3, wherein said LHRH antagonist is administered to a subject in a pharmaceutically acceptable formulation. 14. The method of claim 13, wherein said pharmaceutically acceptable formulation comprises a lipid-based formulation. 15. The method of claim 13, wherein said pharmaceutically acceptable formulation comprises a matrix of a polymer. 16. The method of claim 13, wherein said pharmaceutically acceptable formulation comprises an LHRH antagonist in an insoluble complex with an anionic carrier polymer. 17. The method of claim 16, wherein the LHRH antagonist is about 15-300 μg / k.
4. The method of claim 1, 2, or 3, wherein the method is administered at a dosage of g / day. 18. The method of claim 18, wherein the LHRH antagonist is about 15-200 μg / k.
4. The method of claim 1, 2, or 3, wherein the method is administered at a dosage of g / day. 19. The method of claim 19, wherein the LHRH antagonist is about 15-100 μg / k.
4. The method of claim 1, 2, or 3, wherein the method is administered at a dosage of g / day. 20. The method of claim 1, 2, or 3, wherein the LHRH antagonist is administered continuously using a sustained release formulation. 21. The method of claim 1, 2, or 3, wherein said LHRH antagonist is administered to a subject in combination with at least one other therapeutic agent. 22. A method of inhibiting gynecomastia in a subject, comprising administering to the subject an LHRH antagonist such that gynecomastia is inhibited in the subject. 23. A method of treating a subject for gynecomastia, comprising: (a) selecting a subject in need of treatment for gynecomastia; and (b) providing an LHRH antagonist. Administering to said subject, whereby said subject is treated for gynecomastia. 24. The gynecomastia is the result of a hormonal imbalance.
Or the method of 23. 25. The LHRH antagonist has the structure: Ac-D-Nal ¹ , 4-Cl-D-Phe^Two, D-Pal^Three, N-Me-Tyr^Five, D-Asn⁶,
Lys (iPr)⁸, D-Ala^Ten24.-having LHRH.
The method described in. 26. The LHRH antagonist has the structure: Ac-D-Nal. ¹ , 4-Cl-D-Phe^Two, D-Pal^Three, Tyr^Five, D-Asn⁶, Lys (i
Pr)⁸, D-Ala^Ten24. The method according to claim 22 or 23 having -LHRH.
Law.